Economic evaluation protocol of a short, all-oral bedaquiline-containing regimen for the treatment of rifampicin-resistant tuberculosis from the STREAM trial

Introduction A December 2019 WHO rapid communication recommended the use of 9-month all-oral regimens for treating multidrug-resistant tuberculosis (MDR-TB). Besides the clinical benefits, they are thought to be less costly than the injectable-containing regimens, for both the patient and the health system. STREAM is the first randomised controlled trial with an economical evaluation to compare all-oral and injectable-containing 9–11-month MDR-TB treatment regimens. Methods and analysis Health system costs of delivering a 9-month injectable-containing regimen and a 9-month all-oral bedaquiline-containing regimen will be collected in Ethiopia, India, Moldova and Uganda, using ‘bottom-up’ and ‘top-down’ costing approaches. Patient costs will be collected using questionnaires that have been developed based on the STOP-TB questionnaire. The primary objective of the study is to estimate the cost utility of the two regimens, from a health system perspective. Secondary objectives include estimating the cost utility from a societal perspective as well as evaluating the cost-effectiveness of the regimens, using both health system and societal perspectives. The effect measure for the cost–utility analysis will be the quality-adjusted life years (QALY), while the effect measure for the cost-effectiveness analysis will be the efficacy outcome from the clinical trial. Ethics and dissemination The study has been evaluated and approved by the Ethics Advisory Group of the International Union Against Tuberculosis and Lung Disease and also approved by ethics committees in all participating countries. All participants have provided written informed consent. The results of the economic evaluation will be published in a peer-reviewed journal. Trial registration number ISRCTN18148631.

Background L14-15: I am wondering if the author could include the reference to the claim? L19: There study evaluating the cost-effectiveness of all oral ninemonth bedaquiline containing regimen. Moreover, the WHO consolidated guidelines on tuberculosis Drugresistant tuberculosis treatment Module 4: Treatment Online annexes: Page 125-127, includes analysis on all oral nine months bedaquiline-containing regimen. The uniqueness of the suggested study is that it is the first multi centre economic evaluation study from a randomized phase III trial. L34: Replace the term "a 9-month non-injectable regimen" with "nine months all-oral bedaquiline-containing regimen"? Methods and Analysis General comment: The authors outline a clear and concise process of data collection for STREAM study from a clinical trial perspective. I would recommend the authors also highlight the data collection process for HE data considering that the data collection for Uganda and India has already been collected. Secondly, it would be informative if the authors could include a questionnaire that was used in Uganda and India in the current publication. Randomised controlled trial design Page 7, L16: The authors assume inclusion of a total of 200 participants in the study. For efficacy, the assessment will be based on 200 patients per arm (for each of the arms B, C), but in the objectives of the economic assessment, arm D (6 month injectable regimen) is mentioned too. It is recognized that some countries will have lower recruitment rates, and some participants may not choose to participate in the economic evaluation study. What is the accepted number of participants from each site? How are the authors accounting for potential uncertainty in the estimates? Health system resource use and costs Table 2: • Include the follow-up timeline • Extend the table, including a description data sources Patient costs The authors intend to measure the cost drivers behind the illness and treatment of TB. I strongly suggest to the authors to include the costs components incurred cost of guardians/accompanying persons and lost time HRQoL measurement It is not clear if the study will assess HRQoL scores at baseline? Also, how is the percentage change in score over the treatment period will be compared? Page 9-L58: I suggest to author to include references to existing tools. Page 10-L22: Please provide a reference to the threshold values here.
Page 10:L32: What specific patient data parameters? Include an example, please. Page 10:L52: Do you refer to means and standard deviations? If so, please state that. Page 11: L58: Provided reference to the claim, also include the time points for Covid-19. I also suggest to include the questionnaire if you have already developed one. Page 12: L8: The recruitment for the trial started in 2016. Please specify what sort of data was collected before 2015 that you anticipate to include.

REVIEWER
Ronnie Matambo Biomedical Research and Training Institute, Harare, Zimbabwe REVIEW RETURNED 04-Sep-2020

GENERAL COMMENTS
Dear Authors This writeup clearly shows a lot of effort and attention has been put into this work. The study objectives, study design including the methods are well articulated. Best wishes.

VERSION 1 -AUTHOR RESPONSE
The authors wish to thank the reviewers for expending the time to review our manuscript and for the insightful comments. The authors have made every effort to comply with the comments received. Specific responses are provided below each comment and a revised manuscript with tracked changes submitted.
Specific Comments Abstract • • L52: I suggest to replace the term "a nine-month all oral regimen" with "nine months all-oral bedaquiline-containing regimen" to reflect the title of the publication.
Response: Replaced here and throughout the document • • L53: Include the fact that the data from India and Uganda are to be collected retrospectively. Table 4 P10 that we are referring to the patient cost data that will be collected retrospectively in India and Uganda. We have also explained under the patient costs sub-heading (P8) what data will be collected retrospectively. The newly added paragraph reads: "Due to logistics issues, data collection for the health economic component was delayed at to Indian sites, Ahmedabad and Chennai, and the Ugandan site, so baseline and week 12 patient data will be collected at the week 24 or week 36 visit for the first patients enrolled into the trial. This will be subject to sensitivity analysis. All interviews after week36 will be conducted as scheduled, during the patient assessment visits." Having made these changes in the text we prefer to maintain the abstract as it stands.

Response: We have made it clearer in
Strengths and limitations of this study L32: Replace "an all-oral regimen" with a "nine months all-oral bedaquiline-containing regimen" and throughout the manuscript. Same applies to objectives section, p.6/L34 Response: This has been replaced here and throughout the document L37: The author state that due to the study being collected from multiple settings, resulting in numerous experiences by participants. The author will adjust for the differences in research costs. It is not clear here if the author refers to the charges to conduct the study or the costs recurring for patients and the health system during the study period?
Response: We have provided clarity, showing that we are referring to the research costs in the HE patient and health system analysis. The new sentence now reads: The trial setting means that additional research costs (e.g. costs for collecting pharmacokinetic samples, social support costs paid for by the study) that would not be incurred in a routine setting will be incurred. These research costs will be separated out and eliminated from the costing analysis. Additionally, the experience of participants and delivery of health services (e.g. frequency of visits) will in places, inevitably deviate from routine practice, with implications for patient and health system costs. Though we will attempt to adjust for these differences in analysis, guaranteeing no interference may not be possible. L19: There study evaluating the cost-effectiveness of all oral nine-month bedaquiline containing regimen. Moreover, the WHO consolidated guidelines on tuberculosis Drug-resistant tuberculosis treatment Module 4: Treatment Online annexes: Page 125-127, includes analysis on all oral nine months bedaquiline-containing regimen. The uniqueness of the suggested study is that it is the first multi centre economic evaluation study from a randomized phase III trial.
Response: Sentence has been amended as follows: Furthermore, to date, no phase III trial has included an economic analysis of the nine-month bedaquiline-containing regimen , making it difficult for policymakers to assess the economic and financial impact. STREAM is the first randomised phase III trial to include such an analysis, to compare the all-oral, bedaquiline-containing and injectablecontaining 9-11 month MDR-TB treatment regimens. L34: Replace the term "a 9-month non-injectable regimen" with "nine months all-oral bedaquilinecontaining regimen"?
Response: This has been replaced here and throughout the document Methods and Analysis General comment: The authors outline a clear and concise process of data collection for STREAM study from a clinical trial perspective. I would recommend the authors also highlight the data collection process for HE data considering that the data collection for Uganda and India has already been collected. Secondly, it would be informative if the authors could include a questionnaire that was used in Uganda and India in the current publication.
Response: A new paragraph has been added under the patient costs sub-heading to include details on the data collected retrospectively (P8). Also, two new paragraphs have been added under the Randomised controlled trial design section (P5): Patient data will be collected at 12-week intervals, during the patient assessment visits for the clinical trial, using a questionnaire developed based on the STOP-TB questionnaire, in all HE sites. Health system cost data will be collected by the focal health economists in each country during the whole trial period.
We understand the point regarding the availability of the questionnaire; however, the details of this questionnaire cannot be shared at this time as the trial is ongoing and this instrument is still in use at all sites. We plan to share the questionnaire in a future paper when data analysis has been completed.
Randomised controlled trial design Page 7, L16: The authors assume inclusion of a total of 200 participants in the study. For efficacy, the assessment will be based on 200 patients per arm (for each of the arms B, C), but in the objectives of the economic assessment, arm D (6 month injectable regimen) is mentioned too. It is recognized that some countries will have lower recruitment rates, and some participants may not choose to participate in the economic evaluation study. What is the accepted number of participants from each site? How are the authors accounting for potential uncertainty in the estimates?
Response: Thank you for highlighting this point. All participants, except one, enrolled into the trial at the HE sites have given consent to participate in the HE component. As mentioned on page 4, 'Randomised controlled trial design' section in the manuscript, the sample size was determined by the main trial. This is something we have thought about and decided to present the resuts in terms of precision as explained under the statistical analysis sub-heading. In terms of characterising uncertainty: confidence intervals for the ICER will be calculated, in order to summarise the uncertainty due to sampling variation. Nonparametric bootstrap will be used, based on sampling with replacement from the original data. Confidence intervals will then be constructed using the empirical estimate of the sampling. . This has been made clearer in the manuscript, under the sensitivity analyses subheading. Health system resource use and costs  Table 2 has been extended with a description of data sources included. Additional information on the quantities and the costing methods used have also been added.

Patient costs
The authors intend to measure the cost drivers behind the illness and treatment of TB. I strongly suggest to the authors to include the costs components incurred cost of guardians/accompanying persons and lost time Response: Thanks for the suggestion. Direct costs incurred by guardians/DOT supporters/accompanying persons will be included in the analysis. A new paragraph has been added under the patient costs sub-heading: Usually, TB patients are accompanied by a guardian to the direct observed treatment (DOT) and/or assessment visits. For each patient with a guardian, their guardian's direct costs (transport, food and accommodation costs) will be included in the patient costs analysis. Patients who indicate they had a 'guardian' during treatment will be asked whether this